8-fluoro-2-substituted-gamma-carboline

ABSTRACT

2-(3-Hydroxypropyl)-8-fluoro-1,2,3,4-tetrahydro-5H-pyrido(4,3b)indole has been found to be a powerful anti-depressant when administered to warm-blooded animals.

United States Patent Bernstein et al.

[451 Aug. 29, 1972 [54] 8-FLUORO-2-SUBSTITUTED-GAMMA- CARBOLINE [72]Inventors: Edith Bernstein; David Lyon Garmaise, both of Montreal,Canada; Nicholas Peter Plotnikoff, Lake 21 Appl. No.: 136,194

[52] US. Cl. .....260/295 S, 260/296 A, 260/294.8 B,

424/263, 424/266 [51] Int. Cl. ..C07d 31/42 [58] Field of Search..260/295 S, 296 A [56] References Cited UNITED STATES PATENTS 3,382,2505/1968 Johnson et al ..260/296 A Johnson et al. ..260/296 A Johnson etal ..260/294.9

Primary ExaminerAlan L. Rotman Attorney-Robert L. Niblack [57] ABSTRACT2-( 3-Hydroxypropyl )-8-fluorol ,2,3 ,4-te'trahydro-5H-pyrido[4,3-b]indole has been found to be a powerful anti-depressant whenadministered to warm-blooded animals.

1 Claim, No Drawings 8-FLUORO-2-SUBSTITUTED-GAMMA- CARBOLINE DETAILEDDESCRIPTION OF THE INVENTION a stirred mixture of 8-fluoro-2-carbolinehydrochloride in an inert solvent with a 3-hydroxypropyl halide and anacid acceptor. If desired, a catalyst may be used. The reaction mixtureis evaporated after condensation has been effected and the residue takenup in a suitable, preferably water-immiscible solvent, washed with waterand recovered and recrystallized from ethyl acetate oracetone.

As an illustration but without intention to limit the present invention,the following detailed example is given:

EXAMPLE 8-fluoro-7-carboline 18.1 g. (0.08 moles) and 13.9 g. of3hydroxypropyl bromide (0.1 mole) were stirred and heated at 75-80 C. in250 ml. of dimethylformamide with 22.08 g. of anhydrous potassiumcarbonate (0.16 moles) and 13.28 g. of potassium iodide. After 7 hours,the solvent was evaporated and the residue taken up in 300 ml. ofchloroform and 200 ml. of water. The chloroform layer was separated,washed again with water, dried over magnesium sulfate and evaporatedunder reduced pressure. The brown residue was recrystallized from ethylacetate, yielding 4 g. of 2-(3- hydroxypropyl)-8-fluro-'y-carboline. Ananalytically pure sample was obtained by further recrystallization fromacetone; it melted at 136.5-l 37.5 C.

The anti-depressant activity of this compound was measured by the methodof G. Everett, described in Excerptia Int. Congress, Series 122, page164-7. This test is commonly referred to as modified DOPA-test" and usesan activity scale of l-3 with activity 3 signifying a pronouncedanti-depressant effect. The compound described shows activity 3 at anoral dose of 25 mg./kg.

- in mice after 4 hours and an activity 1 reading after 8 hours; atmg./kg. the test after 4 hours shows the maximum level and activity 2after 8 hours.

The discovery of this activity is quite surprising since derivatives ofthe above compound such as aliphatic esters, inorganic esters such asthe methylsulfonate are orally inactive in the modified DOPA-test.However, acid addition salts of the above compound are equally useful,particularly the non-toxic salts such as the hydrochloride, sulfate,phosphate, succinate, acetate, citrate and tartrate.

We claim:

1. 2-( 3-hydroxypropyl)-8-fluorol ,2 ,3 ,4-tetrahyd ro-5H-pyrido[4,3-b]indole or a non-toxic acid addition salt thereof.

